Carrier screening for Alport syndrome: The clinical importance of heterozygosity for pathogenic or likely pathogenetic variants

Reproductive carrier screening aims to identify individuals at an increased chance of having children affected by genetic conditions. However, testing can also reveal health implications for autosomal or X-chromosome heterozygotes. One such example is screening for Alport syndrome (COL4A3-5-related disease) which is one of the most common causes of inherited chronic kidney disease. Alport syndrome heterozygotes have an increased chance for chronic kidney disease. Monitoring and providing early treatment can slow kidney disease progression and delay the onset of kidney failure. We provide information on Alport syndrome and propose a simple management algorithm for individuals found on carrier screening to have a pathogenic or likely pathogenic variant in one or more of the Alport syndrome genes. We emphasize the importance of genetic counseling, partner screening, and cascade testing to identify at-risk family members, including existing children. Clinical management includes baseline evaluation for kidney disease, nephrology referral when needed, enhanced pregnancy surveillance for proteinuria and hypertension, and long-term follow-up. The proposed management plan serves as an example for other conditions where screening identifies heterozygotes with a variable chance for disease in the individual tested.